Protein kinase C (PKC) is a family of signal transduction proteins that regulate various fundamental cellular processes that are altered in tumors, including cell growth and survival. PKC signaling pathways are, therefore, attractive targets for therapeutic intervention in various cancers. PKC isozymes play a key role in maintenance of intestinal epithelial homeostasis, and altered expression profiles (e.g., loss of PKC alpha and delta, increased levels of PKC iota) have been identified in colon carcinomas. However, understanding of the role of alterations in PKC isozyme signaling in colon carcinogenesis is limited. Strategies are proposed to test the hypothesis that PKC alpha and iota are important survival factors in intestinal epithelial cells (IEC), and that PKC alpha signaling plays a key role in antagonizing the pro-apoptotic effects of PKC delta in this system. Proposed studies aim to (1) Use RNAi to determine the survival and pro-apoptotic signaling mechanisms of PKC alpha and PKC delta, respectively, (2) Determine if restoration of PKC delta expression in colon tumor cells lacking PKC alpha promotes/sensitizes these cells to apoptosis, and (3) Explore the role of PKC iota in survival of human colon tumor cells in the absence/presence of PKC delta expression.